Both
of these radiologic findings have
specific differential diagnoses.
Thickened gastric folds are associated
with malignancy (usually lymphoma,
but poorly-differentiated signet
ring cell gastric carcinoma is also
a possibility), Menetrier's disease,
Zollinger-Ellison syndrome and gastritis.
Hypervascular nodules within the
liver are found with primary liver
disorders (hepatocellular carcinoma,
hemangioma or focal nodular hyperplasia),
or metastatic lesions to the liver
(typically highly vascular tumors
such as renal cell carcinoma, carcinoid
tumor, melanoma, islet cell tumor,
choriocarcinoma, or breast carcinoma).
Two
classic clinical differential diagnoses
are useful for evaluating this case;
that of refractory peptic ulcer,
and that of gastroduodenal ulcers
associated with diarrhea. The differential
diagnosis for refractory peptic
ulcer disease includes Helicobacter
pylori infection, retained gastric
antrum, antral G cell hyperplasia,
gastric malignancy, surreptitious
use of non-steroidal anti-inflammatory
drugs (NSAIDs) and gastrinoma. Helicobacter
pylori infection is acquired by
the fecal-oral route in childhood,
and leads to gastritis via the effects
of specific bacterial cytotoxic
factors (cagA, vacA) and production
of ammonium hydroxide, which leads
to the production of cytokines that
injure the gastric mucosa. The diagnosis
may be established using a rapid
urease test, histologic biopsy,
or culture; the latter is useful
for detecting resistance to antibiotics.
This patient's biopsies were negative,
which argues against Helicobacter
pylori infection. A retained antrum
applies only to patients who have
had prior Bilroth II resections.
In this procedure, the patient has
undergone a gastrojejunostomy, and
the antrum is separated from the
acid-producing body of the stomach.
In the absence of downregulation
by the effects of gastric acid in
its lumen, the antrum hypersecretes
gastrin, leading to hyperacidity
and refractory ulcers. Since this
patient did not undergo this specific
surgical procedure, this possibility
can be easily eliminated. Antral
G-cell hyperplasia reflects an increased
number of gastrin producing G-cells
in the stomach. It is a very rare
cause of recurrent peptic disease,
and approximately 50% of cases are
probably due to occult Helicobacter
pylori infection. A secretin stimulation
test can be useful for distinguishing
G-cell hyperplasia from a neoplasm
of gastrin-producing cells, a gastrinoma.
A gastric malignancy, such as adenocarcinoma
or lymphoma, is always a concern
with a patient with a refractory
gastric ulcer; however, this patient's
biopsies were negative, and the
ulcers also involved the duodenum,
where malignancy would be most unusual.
Surreptitious use of NSAIDs is thought
to cause approximately 40% of "refractory"
peptic ulcer disease. Patients may
not report that they are using NSAIDs,
or be unaware that the over-the-counter
medications that they are taking
contain these agents. NSAIDs cause
gastric toxicity by their topical
irritant effects, and by their inhibition
of prostaglandin synthesis due to
their inhibition of cyclooxygenase
1. This can easily be ruled out
by measuring serum salicylate levels.
The final cause of refractory peptic
disease is a gastinoma. We will
defer discussion of this until later.
The
differential diagnosis for gastroduodenal
ulcers in the face of diarrhea includes
lymphoma, Crohn's disease, vasculitis,
infection and gastrinoma. Enteropathy
associated T-cell lymphomas typically
cause large, shallow ulcerations
leading to secretory diarrhea, and/or
malabsorption. The facts that the
patient lacked constitutional symptoms,
the gastric biopsies were negative,
and the most recent upper endoscopy
was normal, argue against this diagnosis.
Crohn's disease may affect any part
of the gastrointestinal tract. However,
upper GI tract involvement is much
less common than disease in the
ileum and colon, and gastroduodenal
ulceration typically occurs concomitantly
with lower GI tract involvement.
These facts, and the fact that the
gastric biopsies did not show granulomas,
argue against Crohn's disease. Vasculitis
may cause gastroduodenal ulcers
and diarrhea; specific ones to consider
include Behcet's disease and Wegener's
granulomatosis. Behcet's is unlikely
due to the lack of oral or genital
ulcerations, while Wegener's does
not typically lead to severe intestinal
involvement. Infection should always
be considered. Specific agents to
consider include Histoplasmosis,
Cytomegalovirus or Herpes simplex
virus. The absence of systemic involvement,
the absence of a history of immunocompromise,
as well as the absence of constitutional
symptoms argue against these infections.
This brings us to the possibility
of gastrinoma, which also emerged
from the refractory peptic ulcer
disease differential diagnosis as
a leading possibility.
Gastrinoma
is a rare, non- ß islet cell
tumor that secretes gastrin. It
is thought to be the cause of 0.1%-1%
of peptic ulcer disease. Gastrinoma
leads to the characteristic Zollinger-Ellison
Syndrome (ZES) that was first described
in 1955 as peptic ulcer disease,
gastric acid hypersecretion and
the presence of a pancreatic tumor.
The typical symptoms at presentation
for Zollinger-Ellison syndrome include
abdominal pain, reflux and diarrhea.
The abdominal pain in ZES is typically
epigastric, and results from peptic
ulcer disease. Of patients with
ZES with ulcers, 75% of patients
have solitary ulcers, but distal
involvement of the duodenum and
jejunum occurs in the other 25%.
Interestingly, however, 20% have
no evidence of peptic ulcer disease
at presentation. Gastroesophageal
reflux leads to dysphagia and stricture
formation in some of these patients.
Diarrhea may be the sole presenting
symptom in 20% of the patients,
and is largely due to the excessive
amounts of gastric acid secretion.
Patients with ZES secrete an average
of 314 ml an hour of gastric acid
as opposed to the normal 55 ml per
hour. The diarrhea results from
malabsorption due to villus blunting
from the injurious effects of the
acids, and inactivation of pancreatic
enzymes and precipitation of bile
salts by the gastric acid. Specific
clinical clues to that suggest ZES
include recurrent and persistent
ulcers despite acid-suppressive
therapy, persistent diarrhea of
unknown etiology, and multiple ulcers
(specifically distal ulcers) in
the upper gastrointestinal tract.
Histologically, the stomach in ZES
shows a thickened wall (Figure 1)
due to marked Parietal cell hyperplasia
(Figure 2), including Parietal cells
abnormally localized to the superficial
gastric pits (Figure 3).
Figure
1
Figure
2
Figure
3
The
diagnosis of ZES can be made through
several modalities. A fasting serum
gastrin level is the best screening
test, and is elevated in 99% of
patients. It is diagnostic if the
gastrin level is > 1000 and the
gastric pH is < 3. Basal acid
secretion is useful when the gastric
acid is > 15 meq per hour (normal
range is 1.3-4.2). A gastric pH
of > 3 excludes the diagnosis
of ZES. In equivocal cases, a secretin
stimulation test has a sensitivity
of approximately 85%. In a patient
with a gastrinoma, secretin stimulation
results in a paradoxical rise in
serum gastrin levels, which does
not happen in patients with antral
G-cell hyperplasia. Secretin was
unavailable at the time this patient
presented, but has recently again
become available for clinical use.
Several
radiologic studies can be useful
to localizing gastrinomas. 90% or
so of gastrinomas occur in a triangle
which is centered upon the head
of the pancreas, and includes the
gastric antrum and duodenum. An
abdominal CT scan has a sensitivity
of approximately 50%, whereas, an
MRI has a sensitivity of 45%. Selective
angiography has a sensitivity of
40%, and is useful for detecting
the hypervascular pattern of the
gastrinoma. Endoscopic ultrasound
(EUS) has one of the highest sensitivity
of these studies, reaching 85%.
However, the best study for detecting
gastrinoma may be the somatostatin
receptor scintigraphy study. This
study takes advantage of the fact
that neuroendocrine tumors typically
have somatostatin receptors upon
them. Therefore, an octreotide scan,
which uses an analog of somatostatin,
is highly successful in localizing
these neoplasms.
Once
one establishes a diagnosis of Zollinger-Ellison
syndrome, it is important to remember
that 20% of patients with ZES have
the multiple endocrine neoplasia-1
syndrome (MEN-1). This is an autosomal
dominant disorder with high penetrance,
which is characterized by a classic
triad of tumors involving the parathyroid,
endocrine pancreas and anterior
pituitary. Virtually all patients
with MEN-1 have hyperparathyroidism,
so it is important to screen patients
with ZES by checking their serum
calcium levels. In this patient,
the serum calcium was normal.
In
summary, this patient's clinical
course is most compatible with a
gastrinoma. Given the presence of
a liver lesion, the most important
concern is that the liver lesion
represents a metastasis from an
occult primary, though primary hepatic
gastrinomas have been reported.
Clinical
Course:
This
patient had additional serum gastrin
levels drawn, all of which came
back elevated. The highest value
was 900 picograms/mL Importantly,
all of these were taken while the
patient was not taking proton pump
inhibitors, since these agents can
cause a mild elevation of serum
gastrin due to blockage of acid
secretion which diminishes feedback
onto the G-cells. The patient underwent
an octreotide scan which revealed
a solitary left hepatic mass. An
upper endoscopy with endoscopic
ultrasound revealed an acid pH,
despite the fact that the patient
was taking proton-pump inhibitors.
This helped to rule out the possibility
that the gastrin elevation was due
to atrophic gastritis, which would
yield a neutral pH. Importantly,
however, no pancreatic or duodenal
masses were detected on the ultrasound
in the classic gastrinoma triangle.
The
patient was then taken to the operating
room for an intraoperative exploration.
Careful visual examination and palpation,
guided by intraoperative ultrasound,
failed to reveal any tumors aside
from that which was identified in
the left lobe of the liver. The
patient then underwent an uncomplicated
left hepatectomy. This procedure
entailed gaining control of the
blood supply to the left lobe of
the liver (portal vein and hepatic
artery), gaining control of the
left hepatic vein which carries
the liver's outflow of blood to
the vena cava, the transecting then
hepatic parenchyma to remove the
left lobe with the tumor (Figure
4-8). The mass was identified in
segment four of the liver, adjacent
to the left hepatic duct.
Figure
4
Figure
5
Figure
6
Figure
7
Figure
8
Histologic
examination of the resection specimen
revealed a 2cm well-circumscribed,
tan tumor mass within the liver
parenchyma. Microscopic examination
revealed a circumscribed tumor composed
of epithelioid cells with a nested
and trabecular pattern of growth
(Figure 9). The nuclei of the tumor
cells were uniform with "salt
and pepper" type chromatin,
which is typical of neuroendocrine
neoplasms, and neither mitoses nor
necrosis were identified (Figure
10). The neuroendocrine nature of
the tumor was confirmed by immunostaining
for chromogranin (Figure 11)
Figure
9
Figure
10
Figure
11
These
findings are that of a low-grade
neuroendocrine neoplasm within the
liver. On pathologic grounds, this
tumor could be a primary hepatic
carcinoid tumor, a metastatic carcinoid
tumor from the gastrointestinal
tract or a metastatic pancreatic
islet cell tumor.
Clinical
Follow-up
The
patient's postoperative course was
unremarkable. The patient left the
hospital after one week, with normal
liver function tests. The gastrin
level returned to normal at one
month, after which the patient was
asymptomatic off of proton pump
inhibitor therapy.
In
summary, this is a patient who presented
with the Zollinger-Ellison syndrome.
The complete recovery of the patient
after resection of the hepatic lesion
suggests that this was in fact a
rare primary hepatic gastrinoma.
It is still possible that this patient
has within her an occult primary
gastrinoma, and that the hepatic
lesion was a metastasis. If this
were true, one would expect the
patient's symptoms to recur in the
future. This patient will require
complete long-term follow-up to
determine which of these possibilities
is the case.
Return
to Top
|